Existing monotherapies for the treatment of obesity provide only modest weight loss and/or have adverse side effects, and this is also the case with the cannabinoid receptor 1 (CB1) inverse agonist, rimonabant. We aimed to investigate the possibility of improving efficacy and reducing side effects of rimonabant by cotreatment with opioid system antagonists. Using both genetic and pharmacological removal of opioid signaling in mice, we investigated changes in body weight, food intake, and fat mass as well as behavioral outcomes of interactions between opioid ligands and the CB1 using the inverse agonist, rimonabant. The ability of rimonabant to reduce weight is enhanced by removal of with μ-opioid receptor signaling, while not being greatly affected by κ-opioid receptor blockade. Additionally, lack of opioid signaling, especially κ-opioid receptor, attenuated the ability of rimonabant to decrease immobility time in the Porsolt forced-swim test, a preclinical model of depression. These results indicate that the endogenous opioid system is involved in modulating both the metabolic and mood effects of rimonabant.
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